Peptide-induced negative activates transcription of selection of thymocytes an NF-κB inhibitor

Negative selection eliminates thymocytes bearing autoreactive T cell receptors (TOR) via an apoptotic mechanism. We have cloned an inhibitor of NF-kappaB, IkappaBNS, which is rapidly expressed upon TCR-triggered but not dexamethasone- or gamma irradiation-stimulated thymocyte death. The predicted protein contains seven ankyrin repeats and is homologous to IkappaB family members. In class I and class II MHC-restricted TOR transgenic mice, transcription Of IkappaBNS is stimulated by peptides that trigger negative selection but not by those inducing positive selection (i.e., survival) or nonselecting peptides. IkappaBNs blocks transcription from NF-kappaB reporters, alters NF-kappaB electrophoretic mobility shifts, and interacts with NF-kappaB proteins in thymic nuclear lysates following TOR stimulation. Retroviral transduction Of IkappaBNS in fetal thymic organ culture enhances TCR-triggered cell death consistent with its function in selection.